1. Field of the Invention
The present invention relates generally to compounds and methods for modulating chloride ion transport, and, more specifically, to antagonists and agonists of inositol polyphosphates.
2. Background Information
All living organisms are made of cells. The boundary of a cell is determined by the plasma membrane which serves to segregate materials on the inside from those on the outside. The cell membrane functions by regulating the passage of materials such as nutrients into or out of the cell. The transport of ions across cell membranes serves many important functions in a cell, including the regulation of oncotic pressure of the cell. The regulation of ion transport provides cells with the appropriate concentration of ions to maintain their integrity and function. Under inappropriate conditions, for example, if the ion concentration inside the cell is too high, water moves into the cell and causes it to swell or burst. If the ion concentration in the cell is too low, the cell shrinks.
Organisms exploit the cell membrane ion transport properties to regulate fluids in particular tissue types. For example, cells lining the intestine regulate water uptake using ion transport. One particularly important ion transported by cells is chloride ion. Chloride ion transport plays a key role in a variety of cellular functions such as osmoregulation, intracellular pH regulation, and salt and fluid secretion.
In the intestine, high levels of chloride ion secretion are associated with diseases such as secretory diarrhea. Secretory diarrhea has many causes, including infection by microorganisms such as Salmonella, Shigella, and certain strains of Escherichia coli. Other conditions associated with the regulation of fluid levels in tissues and chloride ion secretion include tissue swelling associated with inflammation, infection or trauma. Thus, methods for inhibiting undesirable levels of chloride ion secretion could be used to alleviate symptoms of these pathologies.
Cystic fibrosis is the most common lethal genetic disease in Caucasians, affecting approximately one in 2,000 births among Americans of European descent. It is characterized by abnormally viscous mucous secretions, which lead to chronic pulmonary disease, pancreatic insufficiency and intestinal obstructions. In the United States, approximately 30,000 people have cystic fibrosis and about 1,000 new cases are diagnosed every year. Although, in the past, afflicted children often died as infants, individuals can now survive into their twenties and thirties. Nevertheless, there is no cure for cystic fibrosis and current therapies do not correct the underlying cellular defect but only manage the symptoms of the disease.
Current treatments for cystic fibrosis are largely confined to symptom management or control of opportunistic infections. For example, the use of vaccinations for viral pathogens and culture-specific antibiotics for bacterial infections can be used to prevent infection. Corticosteroids are sometimes useful in the treatment of the inflammatory response to infections but have a variety of undesirable long term side effects. Other treatments focus on the symptoms of chronic pulmonary disease associated with abnormally viscous mucous secretions in the lung. For example, physical assistance such as chest percussion and postural drainage aids in clearing the secretions from the lungs. Bronchodilators have been beneficial in some patients, but in others have resulted in decreased gas exchange. Other symptoms associated with abnormally viscous mucous secretions include intestinal obstructions and pancreatic insufficiency. Intestinal obstructions occur in 20% of adults and are treated with enemas, or, where enemas are not effective, by surgery.
Pancreatic insufficiency occurs in 80 to 90% of the patients and is caused by decreased secretion of bicarbonate ions and fluid due to impaired recycling of chloride ions out of the cell. The corresponding pancreatic fluid becomes hyperconcentrated in protein and becomes inspissated, causing obstruction of the pancreatic ducts and subsequent atrophy of pancreatic acini. Pancreatic insufficiency is treated with enzyme supplementation, which usually restores adequate digestive and absorptive functions, thereby correcting symptoms of malnourishment. However, the underlying disease persists, often causing recurrent bouts of pancreatitis that can lead to atrophy of the pancreas.
A treatment that restores normal pulmonary function, normal secretory function to the colon or normal pancreatic function would provide a great advantage over currently available therapies. Gene therapy has been used on cystic fibrosis patients. However, attempts at gene therapy have been unsuccessful for a variety of reasons, including the extraordinary size of the gene, immune reactions to adenovirus vectors used to transfer the gene and the rapid turnover of epithelial tissue.
Thus, there exists a need for a means to alter chloride ion secretion so as to ameliorate the symptoms of pathologies such as cystic fibrosis and secretory diarrhea which are associated with abnormal chloride transport. The present invention satisfies this need and provides related advantages as well.